Diabetes is one of important adult diseases all over the world, and in Korea, it reaches a prevalence rate of 7-8% with rapid economic growth and becomes an important cause of death of people in the 60-70-year-old age group. Diabetic complication, a cause of death by diabetes, occurs by the damage of almost all organs in the body at 10-20 years after the onset of diabetes, and is expressed as diabetic retinopathy, diabetic cataract, diabetic nephropathy, diabetic neuropathy, etc. Particularly, chronic diabetic nephropathy is the most important cause of end-stage renal disease and cannot be treated by other therapies than blood dialysis therapy and organ transplantation. This diabetic complication can progress even when diabetes is cured so as to recover the normal blood glucose concentration. This diabetic complication is known to be caused mainly by advanced glycation endproducts (AGEs) irreversibly produced as a result of the nonenzymatic glycation of protein due to the continuation of a high blood glucose condition.
Mechanisms of causing this diabetic complication are broadly described as the nonenzymatic glycation of protein, polyol pathways, oxidative stress, etc.
The nonenzymatic glycation of protein is caused by the nonenzymatic condensation of the amino acid groups (e.g., lysine residues) of protein with glucose, which produces advanced glycation endproducts (AGEs). The nonenzymatic glycation of protein can consist of the following two steps: (1) the amino acid groups (e.g., lysine residues) of protein, and the aldehydes or ketones of glucose, are subjected to nucleophilic addition reaction without the action of enzymes so as to form Schiff bases as early-stage products, and ketoamine adducts adjacent to the Schiff bases are condensed with each other to produce reversible Amadori-type early glycation products; and (2) by the continuation of a high blood glucose condition, the reversible Amadori-type early glycation products are rearranged without degradation and cross-linked with proteins, thus producing advanced glycation endproducts.
Unlike the reversible Amadori-type early glycation products, the advanced glycation endproducts are irreversible. Thus, even when blood glucose is recovered to a normal level, the endproducts, once produced, are accumulated in tissues during a protein existing period without degradation, resulting in an abnormal change in the structure and function of the tissues (Vinson, J. A. et al., 1996, J. Nutritional Biochemistry 7: 559-663; Smith, P. R. et al., 1992, Eur. J. Biochem., 210: 729-739).
For example, glycated albumin, one of advanced glycation endproducts produced by the reaction of glucose with various proteins, acts as an important factor of causing chronic diabetic nephropathy. The glycated albumin is introduced into glomerular cells more easily than non-glycated normal albumin, and a high concentration of glucose stimulates glomerular cells to increase the synthesis of extracellular matrices. The excessive introduction of glycated albumins and the increase of extracellular matrices result in the fibrillation of glomerules. By such mechanisms, the glomerules are continuously damaged, eventually making the use of an extreme treatment method, such as blood dialysis or organ transplantation, unavoidable. Also, it was reported that, due to chronic diabetes, collagens are accumulated on the arterial wall, and basement membrane proteins are accumulated on glomerules by binding to advanced glycation endproducts (Brownlee, M., et al., 1986, Sciences, 232, 1629-1632).
As described above, the nonenzymatic protein glycation leads to the glycation of basement membranes, serum albumins, lens proteins, fibrins, collagens, etc., and the advanced glycation endproducts cause an abnormal change in the structure and function of the tissues, resulting in chronic diabetic complications, such as diabetic retinopathy, diabetic cataract, diabetic nephropathy, diabetic neuropathy, etc.
Moreover, it is known that the advanced glycation endproducts produced in the nonenzymatic protein glycation also play an important role in aging (Monnier et al., Proc. Natl. Acad. Sci. USA, 81: 583, 1984; Lee et al., Biochem. Biophys. Res. Comm., 123: 888, 1984; Diabetologia, 38: 357-394).
As described above, the advanced glycation endproducts produced in the nonenzymatic protein glycation are main factors in the progression of diabetic complication and aging. Thus, to prevent the progression of diabetic complication and aging, the production of advanced glycation endproducts need to be inhibited.
Currently, the only synthetic drug as a protein glycosylation inhibitor is aminoguanidine, a nucleophilic hydrazine, which prevents Amadori products from crosslinking with proteins, by binding to the Amadori products, so as to inhibit the production of advanced glycation products, thus delaying or preventing the development of diabetic complication (Brownlee, M., et al., 1986, Sciences, 232, 1629-1632; Edelstein, D. et al., 1992, Diabetes, 41, 26-29). The aminoguanidine, which is the most promising synthetic drug candidate for the prevention and treatment of diabetic complication, was developed up to third-phase clinical trials but has the problem of causing toxicity upon long-term administration. Thus, the development of safer drugs is now needed.
Accordingly, due to limitations in disease-treating agents with the existing synthetic compounds and the problems of side-effects and toxicity in the application of such treating agents, the development of disease-treating agents based on medicinal herbal formulations are now actively conducted.
Thus, during studies on medicinal herbal materials for the prevention and treatment of diabetic complication and aging, the present inventors have found that Euphorbiae radix, gingered Magnolia bark, parched Puerariae radix and Glycyrrhizae radix are effective for inhibiting the production of advanced glycation endproducts, and particularly, a mixture consisting of these herbal materials at an amount of each herbal material of 5-85% by weight based on the total weight of the herbal materials taken as 100% by weight, and magnolol isolated from Magnolia bark, have an excellent effect on the inhibition of production of advanced glycation endproducts and thus, are useful for not only the prevention and treatment of diabetic complication but also the prevention and delay of aging. On the basis of these findings, the present invention has been completed.